1. Field of the Invention
The invention relates to the field of medical technology, and more particular to a method for synthesizing temsirolimus.
2. Description of the Related Art
mTOR kinase is an important protein to control cell proliferation, growth, and survival. As a medicine for treating kidney cancers, temsirolimus is able to inhibit mTOR kinase, lower the level of some angiogenesis factors, such as the vascular endothelial growth factor, inhibit the growth of new vessels, and finally lead to the death of cancer cells.
A typical method for preparing temsirolimus is shown in FIG. 2. The method includes: carrying out reaction between 2,2-dimethylol propionic acid and 2,4,6-trichlorobenzoyl chloride under the protection of 2,2-dimethoxypropane to yield an anhydride; condensing the anhydride with rapamycin, separating intermediate A-1, and finally removing a protecting group to yield temsirolimus. However, the method has defects that it is difficult to separate a product from a by-product produced by synchronous esterification of 31- and 42-hydroxyls, and the total yield is only 20%.
An improved synthetic method is shown in FIG. 3. The method includes: protecting the 31- and 42-hydroxyls by trimethylchlorosilane; selectively removing a 42-protecting group to yield intermediate B-1; carrying out a condensation reaction between the intermediate B-1 and the anhydride; and finally removing a 32-protecting group to yield temsirolimus. Although the yield of the method is increased to 47%, the method has multiple reaction steps and a complicate process.
Further improvement is shown in FIG. 4, including: protecting 2,2-dimethylol propionic acid by phenylboronic acid, and removing the protecting group by 2-methyl-2,4-pentanediol to yield temsirolimus. And another improved method is shown in FIG. 5. The method includes: enzyme catalyzing rapamycin, carrying out reaction between 42-hydroxyl radical of rapamycin and alkyl group protected 2,2-dimethylol propionic acid, and removing the protecting group to yield temsirolimus. The method has high yield, but high production cost.
Thus, methods for synthesizing temsirolimus in the prior art are disadvantageous in low yield, multiple reaction steps, complicate process, and high production cost.